This Mentored Patient-Oriented Research Career Development Award will provide Dr. Arielle Stanford with the training and skills needed to become an independent investigator with expertise in the development of treatments targeting the negative symptoms of schizophrenia. Negative symptoms are among the strongest predictors of poor outcome and are not very responsive to treatment. Novel treatments are needed to alleviate these symptoms and improve functioning. Most treatment studies have not focused on the large between-patient variability in phenomenology and etiology that may contribute to reduced response rates. This project will evaluate the potential utility of repetitive transcranial magnetic stimulation (rTMS) as an intervention that may test etiological hypotheses linked to heterogeneity and treat negative symptoms. While it has been difficult to meaningfully separate schizophrenia disease variants, there are subgrouping strategies that could be explored with respect to negative symptoms, including the division of patients into Deficit Syndrome (DS) and nonDS groups, and data supporting Paternal Age Related Schizophrenia (PARS) as an independent variant. Studies suggest that different types of negative symptoms map to disparate neural circuits. Thus, noninvasive focal brain stimulation may have specific advantages over medications, which lack spatial resolution. rTMS can modulate neuronal activity and produce regionally specific excitatory or inhibitory effects through modulation of local physiology and chemistry. The efficacy of rTMS may be enhanced by site-specific application targeted to patient subgroups. None of the existing studies of rTMS in schizophrenia have entailed full characterization of patients, nor has DS been considered as a response mediator. Lastly, studies of negative symptoms have only targeted the DLPFC, omitting the potential role of other cortical regions. The aims of this Mentored Patient-Oriented Research Career Development Award are to 1) to examine the efficacy and safety of rTMS as a treatment for the negative symptoms of schizophrenia and 2) to characterize responders vs. non-responders to rTMS with respect to etiological subgroup (DS vs. non-DS) and other baseline characteristics, including cognitive and demographic, using the focality of rTMS as a brain probe to test hypotheses regarding the neural underpinnings of negative symptoms. The candidate's career goal is to develop novel treatment strategies tailored to the symptom profile and schizophrenia subtype of the patient, i.e. to shape this novel intervention to the heterogeneity of schizophrenia. The career development plan will provide expertise in: 1) the neurocircuitry of negative symptoms, 2) the use of TMS as a neurobiological probe and as a treatment tool; and 3) clinical trial research design and statistical analysis. This training and research experience will position Dr. Stanford to become an independent investigator in the field of intervention development in the study and treatment of schizophrenia. [unreadable] [unreadable] [unreadable]